<i>N</i>‐(furan‐2‐ylmethyl)‐<i>N</i>‐methylprop‐2‐yn‐1‐amine (F2<scp>MPA</scp>): A Potential Cognitive Enhancer with <scp>MAO</scp> Inhibitor Properties

Giovanni, Giuseppe Di; García, Isela; Colangeli, Roberto; Pierucci, Massimo; Rivadulla, Marcos L.; Soriano, Elena; Chioua, Mourad; Corte, Laura Della; Yáñez, Matilde; Deurwaerdère, Philippe De; Fall, Yagamare; Marco‐Contelles, José

doi:10.1111/cns.12284

Cited by 9 publications

(21 citation statements)

References 39 publications

(57 reference statements)

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“…Moreover, while 3-MT would generate few off targets on its own 23 Intracerebral microdialysis is a much more sensitive approach for the study of MAO A function compared to tissue measurement as exemplified in this study with clorgyline. The finding that F2MPA altered neither basal nor 3-MT-stimulated extracellular levels of HVA in contrast to clorgyline suggests that the effects reported previously in vivo 12 or in this study ex vivo are unrelated to MAO inhibition. Nonetheless, MAOIs administered acutely have complex and regional effects on monoamine content 13 .…”

Section: Resultscontrasting

confidence: 75%

“…Based on the previous study reporting a strong effect of F2MPA at 1 mg/kg 12 , we selected the doses of 1 and 4 mg/g for all drugs (Table 1). Although all compounds significantly enhanced 5-HT content in the cortex, the main result is that all compounds exhibited a distinct profile on monoamine tissue content.…”

Section: Resultsmentioning

confidence: 99%

“…A combination of neurochemical, metabolic and biochemical studies were performed to dissect the MAO inhibitory properties of F2MPA, a propargyl-containing compound that was previously (Table 2), it can be concluded that the pro-cognitive profile of F2MPA described earlier 12 could be related to a still unknown action on monoamine systems, which is independent from its very poor MAO inhibition properties. A full pharmacological description of its binding profile on various receptors, enzymes and transporters is still not available, impairing any further comments on its mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

“…Historically, MAO A and MAO B are specifically inhibited by clorgyline and deprenyl, respectively, both being propargyl amines which irreversibly and covalently inactivate the enzymes. In 2014, we reported a new inhibitor of this class, N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA, Figure 1), which showed enhancement of basic synaptic transmission in the hippocampus of rats 12 . In that report, F2MPA had a striking effect on the rat dentate gyrus electrophysiology, similar to that of the long-lasting potentiation effect of NE.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Deurwaerdère

Binda

Corne

et al. 2016

ACS Chem. Neurosci.

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The regulation of brain monoamine levels is paramount for cognitive functions and the enzymes monoamine oxidases (MAO A and B) play a central role in these processes. The aim of this study was to evaluate whether the pro-cognitive properties exerted by propargylamine N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA) were related to changes in monoamine content via MAO inhibition. In vivo microdialysis and ex vivo amine metabolite measurement demonstrated region-specific alterations in monoamine metabolism that differ from both the classic MAO A or MAO B inhibitors clorgyline and L-deprenyl, respectively. Although all the inhibitors (1 and 4 mg/kg) increased cortical serotonin tissue content, only F2MPA increased the levels of cortical noradrenaline. In the striatum, clorgyline (1 mg/kg), but not F2MPA (1 mg/kg), reduced extracellular levels of dopamine metabolites at rest or stimulated by the intrastriatal application of the MAO substrate 3-methoxytyramin. In vitro, F2MPA exhibited a low affinity toward MAO B and MAO A. Nonetheless, it modified the B form of MAO, forming a flavin adduct structurally similar to that with deprenyl. F2MPA was rapidly metabolized in the presence of rat, but not human, microsomes, producing a hydroxylated derivative. In conclusion, the effect of F2MPA on cognition may arise from monoaminergic changes in the cortex, but the role of MAO in this process is likely to be negligible, consistently to the F2MPA poor affinity for MAO.

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Section: Resultscontrasting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Deurwaerdère

Binda

Corne

et al. 2016

ACS Chem. Neurosci.

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“…In detail, scaffolds containing a propargylamine moiety are of particular interest due to their reported beneficial actions 18,19 . In a previous work we have demonstrated that the concurrent inhibition of this enzyme and the binding to the 5-HT3 receptor can lead to interesting compounds 20 .…”

Section: Introductionmentioning

confidence: 99%

(Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies

D’Ascenzio

Chimenti

Gidaro

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Department of Pharmacy, ''G. D'Annunzio'' University of Chieti-Pescara, Chieti Scalo (CH), Italy Abstract Several (thiazol-2-yl)hydrazone derivatives from 2-, 3-and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure-activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases.

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Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors

Altıntop

Sever

Osmaniye

et al. 2018

Archiv der Pharmazie

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In an effort to develop potent monoamine oxidase (MAO) inhibitors, new pyrrole derivatives were obtained via the selective reduction of the CC bonds of 1-(1-methyl-1H-pyrrol-2-yl)-3-[5-(aryl)furan-2-yl]prop-2-en-1-ones through palladium catalyzed hydrogenation in ethanol. The synthesized compounds were screened for their inhibitory effects on MAO-A and MAO-B by an in vitro fluorometric method. The selectivity index (SI) value was given as the ratio of IC (MAO-A)/IC (MAO-B) for each compound. 3-(5-(4-Chlorophenyl)furan-2-yl)-1-(1-methyl-1H-pyrrol-2-yl)propan-1-one (6) was identified as the most selective MAO-A inhibitor in this series, with an IC value of 0.162 µM and a SI value of 0.002. Kinetic studies were also carried out to assess the nature of MAO-A inhibition by compound 6. According to Lineweaver-Burk plots, compound 6 was found to be a competitive MAO-A inhibitor and the K value of compound 6 was determined as 0.1221 μM. Docking studies were performed for compound 6 and clorgyline using the human MAO-A crystal structure (PDB ID: 2Z5Y). The docking results showed that compound 6 presented similar interactions as clorgyline in the active center cavity of the enzyme. Molinspiration software was used to determine the physicochemical parameters of all compounds for an evaluation of their compliance to Lipinski's rule of five. Compound 6 did not violate Lipinski's rule, making it a potential orally bioavailable therapeutic agent.

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N‐(furan‐2‐ylmethyl)‐N‐methylprop‐2‐yn‐1‐amine (F2MPA): A Potential Cognitive Enhancer with MAO Inhibitor Properties

Abstract: Our findings suggest that, the MAO-B inhibitor, F2MPA improves DG synaptic transmission without triggering pathological hyperexcitability. Therefore, F2MPA shows promise as a potential cognition-enhancing therapeutic drug.

Cited by 9 publications

References 39 publications

Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

(Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies

Design, synthesis, in vitro and in silico evaluation of new pyrrole derivatives as monoamine oxidase inhibitors

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